Tissue treatment methods

ABSTRACT

Methods are provided herein for affecting a region of a subject&#39;s body, comprising exposing the region to a cooling element under conditions effective to cool subcutaneous adipose tissue in said region; and increasing the blood flow rate to the cooled tissue by exposing the tissue to an energy source. Methods are also provided for treating subcutaneous adipose tissue in a region of a subject&#39;s body, comprising exposing said region to a cooling element under conditions effective to cool said tissue; and exposing the tissue to an energy source to increase the blood flow rate to the cooled tissue, thereby stimulating reperfusion in, and/or causing an ischemia-reperfusion injury to, the cooled tissue.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 11/528,225,filed Sep. 26, 2006, entitled “Cooling Devices Having a Plurality ofControllable Cooling Elements to Provide a Predetermined CoolingProfile” the entire disclosure of which is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates generally to methods for treatingmammalian tissue, to subcutaneous adipose tissue treatment methods, andparticularly to those involving cooling of the tissue.

BACKGROUND OF THE INVENTION

Excess body fat increases the likelihood of developing various types ofdiseases such as heart disease, high blood pressure, osteoarthrosis,bronchitis, hypertension, diabetes, deep-vein thrombosis, pulmonaryemboli, varicose veins, gallstones, hernias, and several otherconditions.

In addition to being a serious health risk, excess body fat can alsodetract from personal appearance and athletic performance. For example,excess body fat can form cellulite, which causes an “orange peel” effectat the surface of the skin. Cellulite forms when subcutaneous fatprotrudes into the dermis and creates dimples where the skin is attachedto underlying structural fibrous strands. Cellulite and excessiveamounts of fat are often considered to be unappealing. Thus, in light ofthe serious health risks and aesthetic concerns associated with excessfat, an effective way of controlling excess accumulation of body fat isurgently needed.

Liposuction is a method for selectively removing body fat to sculpt aperson's body. Liposuction is typically performed by plastic surgeonsand dermatologists using specialized surgical equipment thatmechanically removes subcutaneous fat cells via suction. One drawback ofliposuction is that it is a serious surgical procedure, and the recoverymay be painful. Liposuction can have serious and occasionally even fatalcomplications. In addition, the cost for liposuction is usuallysubstantial.

Conventional non-invasive treatments for removing excess body fattypically include topical agents, weight-loss drugs, regular exercise,dieting, or a combination of these treatments. One drawback of thesetreatments is that they may not be effective or even possible undercertain circumstances. For example, when a person is physically injuredor ill, regular exercise may not be an option. Similarly, weight-lossdrugs or topical agents are not an option when they cause an allergic ornegative reaction. Furthermore, fat loss in selective areas of aperson's body cannot be achieved using general or systemic weight-lossmethods.

Other non-invasive treatment methods include applying heat to a zone ofsubcutaneous lipid-rich cells. U.S. Pat. No. 5,948,011 disclosesaltering subcutaneous body fat and/or collagen by heating thesubcutaneous fat layer with radiant energy while cooling the surface ofthe skin.

Another method of reducing subcutaneous fat cells is to cool the targetcells as disclosed in U.S. Patent Publication No. 2003/0220674 or inU.S. Patent Publication No. 2005/0251120, the entire disclosures ofwhich are incorporated herein. These publications disclose, among otherthings, reducing the temperature of lipid-rich subcutaneous fat cells toselectively affect the fat cells without damaging the cells in theepidermis. Although these publications provide promising methods anddevices, several improvements for enhancing the implementation of thesemethods and devices would be desirable.

In medicine, ischemia is a restriction in blood supply, generally due tofactors in the blood vessels, with resultant damage or dysfunction oftissue. Since oxygen is mainly bound to hemoglobin in red blood cells,insufficient blood supply causes tissue to become hypoxic, or, if nooxygen is supplied at all, anoxic. This can cause necrosis and celldeath. Ischemia is a feature of heart diseases, transient ischemicattacks, cerebrovascular accidents, ruptured arteriovenousmalformations, and peripheral artery occlusive disease. Tissues that areespecially sensitive to inadequate blood supply include the heart, thekidneys, and the brain.

Restoration of blood flow after a period of ischemia is generallyrecognized to actually be more damaging than the ischemia itself. Theabsence of oxygen and nutrients from blood creates a condition in whichthe restoration of circulation results in inflammation and oxidativedamage from the oxygen (i.e., reperfusion injury) rather thanrestoration of normal function. Reintroduction of oxygen also causes agreater production of damaging free radicals. With perfusion injury,necrosis can be greatly accelerated.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides methods and devices thatuse ischemia-reperfusion injury to reduce or eliminate fat cells in thehuman body. Although it is generally considered desirable to minimizeischemia-reperfusion injury to cells in the human body, it is believed,while not intending to be bound by theory, that it is beneficial toeffect ischemia-reperfusion injury in adipose tissue, thus enhancingadipose tissue necrosis or apoptosis.

In certain embodiments, the present invention thus provides methods foraffecting a region of a subject's body, comprising exposing an epidermallayer in said region to a cooling element under conditions effective tocool subcutaneous adipose tissue in said region; and increasing the rateof blood flow to the cooled tissue by exposing the tissue to an energysource.

In another embodiment, the invention provides methods of treatingsubcutaneous adipose tissue in a region of a subject's body, comprisingexposing said region to a cooling element under conditions effective tocool said tissue; and stimulating reperfusion in the cooled tissue byexposing the tissue to an energy source to increase the blood flow rateto the cooled tissue.

The present invention also provides methods of treating subcutaneousadipose tissue in a region of a subject's body, comprising exposing saidregion to a cooling element under conditions effective to cool saidtissue; and causing an ischemia-reperfusion injury to the cooled tissueby exposing the tissue to an energy source to increase the blood flowrate to the cooled tissue.

In still another embodiment, the present invention provides coolingmethods for selective reduction of lipid-rich cells in a region of ahuman subject's body, comprising applying a cooling element proximal tothe subject's skin to reduce the temperature within a local regioncontaining the lipid-rich cells sufficiently to selectively reduce thelipid-rich cells of said region, and concurrently therewith maintain thesubject's skin at a temperature wherein non-lipid-rich cells proximateto the cooling element are not reduced; and subsequent to applying acooling element, applying an energy source to the cooled tissue tothereby increase a rate of blood flow to the cooled tissue.

In another embodiment, the present invention provides methods forselective reduction of lipid-rich cells in a region of a human subject'sbody, comprising selectively causing vasoconstriction in adipose tissue;and subsequently stimulating reperfusion by applying an energy source tothereby increase blood flow to the region.

Instill another embodiment, the present invention provides methods forselectively creating ischemia in lipid-rich cells in a region of a humansubject's body, and subsequently stimulating reperfusion by applying anenergy source to thereby increase the blood flow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic of a system for providing cooling or heating to asubject according to one embodiment of the present invention.

FIG. 2 is a schematic of a fluid control unit for the system of FIG. 1 .

FIG. 3 is a schematic of an alternative fluid control unit for thesystem of FIG. 1 .

FIG. 4 shows an alternative system for providing cooling or heating to asubject.

FIGS. 5-8 are isometric views of a temperature control device.

FIG. 9 is an exploded isometric view of the temperature control deviceof FIG. 5 .

FIG. 10 is a block diagram showing computing system software modules forremoving heat from subcutaneous lipid-rich cells in accordance with anembodiment of the invention.

The figures are provided by way of example and are not intended to belimiting.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

In one embodiment, the present invention provides methods for affectinga region of a subject's body, comprising exposing an epidermal layer insaid region to a cooling element under conditions effective to coolsubcutaneous adipose tissue in said region; and increasing the bloodflow rate to the cooled tissue by exposing the tissue to an energysource.

In certain embodiments, the methods further comprise cycling at leastone of the steps of exposing said region to a cooling element andincreasing blood flow. For example, after a cycle of exposing saidregion to a cooling element and increasing blood flow, a step ofexposing said region to a cooling element could be repeated.Alternatively, a step of increasing blood flow could be added.

In certain embodiments, the methods of the invention further compriseincreasing vasoconstriction in the adipose tissue. This can be achievedby various mechanical, chemical means or certain cooling conditions.Certain drugs can be administered orally or injected into the adiposetissue to increase vasoconstriction. Epinephrine is an example of onevasoconstrictive drug that is commonly injected. Other examples includenorepinephrine, catecholamines, epinephrine isoproterenol, dopamine,ephedrine, phenylephrine, amphetamine, metraminol, methoxamine, ergotalkaloids, ergonovine, methylergonavine, methysergide, and ergotamine. Amechanical means for increasing vasoconstriction would be by applicationof pressure to the region.

For purposes of this specification, “affecting” means affecting,disrupting, shrinking, disabling, destroying, removing, killing, orotherwise being altered. As mentioned above, cooling subcutaneousadipose tissue may result in disruption and eventual death of theadipocytes.

The term “subject,” as used herein, includes any animal having blood,adipose tissue, and an epidermis. In preferred embodiments, the subjectis a human or some other mammal, even more preferably a non-infanthuman.

The term “temperature control element” refers to any structure that isable to effect an increase or reduction in temperature of an area orobject of interest. A temperature control element that effects areduction in temperature is, thus, a “cooling element.” In oneembodiment, the temperature control element is actively cooled orheated, as with a fluid bath or the Peltier (thermoelectric) elementsthat are known in the art to create cold and warm surfaces dependentupon the application of voltage. FIG. 1 shows one type of active coolingor heating system 10, comprising a hot bath 12 and a cold bath 14 influid communication with an applicator 16. It is understood that theterm bath is not intended to limit the fluid to water. For example, thecold bath 14 could receive a fluid comprising alcohol, glycol, ormixtures of water/alcohol or water/glycol. The baths include heating orcooling means, temperature sensors, and feedback control systems tomaintain selected temperatures. In one embodiment, the hot bath is about45° C. and the cold bath is about −5° C.

Depending on the type of fluids circulated through the applicator 16, awide temperature range can be achieved at the applicator 16. Theapplicator 16 can be formed from a variety of thermoconductivematerials, including copper, aluminum, or alloys, and is applied to asubject's epidermis. Alternatively, the applicator 16 could be formedfrom a relatively thin layer of nonconductive material, such asurethane. A fluid control unit 18 is disposed between the baths and theapplicator to control the applicator temperature.

FIG. 2 provides a schematic for the fluid control unit 18, includingfluid lines, a pump, a pair of valves, and logic (not depicted) foropening and closing the valves. In one embodiment, when cooling isdesired, the valves route the fluid from the cold bath 14 to the pump,which circulates the fluid through the applicator and then back to thecold bath. Similarly, when heating is desired, the valves route thefluid from the hot bath 12 to the pump, which circulates the fluidthrough the applicator and then back to the hot bath.

Referring to FIG. 3 , an alternative fluid control unit 18′ is depicted,including fluid lines, a pump, three valves, and logic (not depicted)for opening and closing the valves. In one embodiment, when cooling isdesired, Valve 2 is opened, while valves Valve 1 and V3 are shut. Thus,the pump draws the fluid from the cold bath 14, which circulates thefluid through the applicator 16 and then back to the cold bath through afluid long loop 20. It is understood that fluid long loop 20 is of asufficient length and/or diameter that when valve V3 is open, the vastmajority of the fluid passes through valve V3 and out to the hot bath12. However, when valve V3 is closed, the system pressure drives thefluid through the long loop 20 and to the cold bath 14.

FIG. 4 depicts another system 100 for removing heat from subcutaneouslipid-rich cells of a subject 101 in accordance with the invention. Thesystem 100 can include a cooling device 104 placed at an abdominal area102 of the subject 101 or another suitable area for removing heat fromthe subcutaneous lipid-rich cells of the subject 101.

The system 100 can further include a cooling unit 106 and supply andreturn fluid lines 108 a-b connecting the cooling device 104 to thecooling unit 106. The cooling unit 106 can remove heat from a coolant toa heat sink and provide a chilled coolant to the cooling device 104 viathe fluid lines 108 a-b. Examples of the circulating coolant includewater, glycol, synthetic heat transfer fluid, oil, a refrigerant, andany other suitable heat conducting fluid. The fluid lines 108 a-b can behoses or other conduits constructed from polyethylene, polyvinylchloride, polyurethane, and other materials that can accommodate theparticular circulating coolant. The cooling unit 106 can be arefrigeration unit, a cooling tower, a thermoelectric chiller, or anyother device capable of removing heat from a coolant. Alternatively, amunicipal water supply (i.e., tap water) can be used in place of thecooling unit.

The cooling device 104 includes a plurality of thermoelectric coolingelements, such as Peltier-type thermoelectric elements, which can beindividually controlled to create a custom spatial cooling profileand/or a time-varying cooling profile. The system 100 can furtherinclude a power supply 110 and a processing unit 114 operatively coupledto the cooling device 104. In one embodiment, the power supply 110 canprovide a direct current voltage to the thermoelectric cooling device104 to effectuate a heat removal rate from the subject 101. Theprocessing unit 114 can monitor process parameters via sensors (notshown) placed proximate to the cooling device 104 through power line 116to adjust the heat removal rate based on the process parameters. Theheat transfer rate can be adjusted to maintain constant processparameters. Alternately, the process parameters can vary eitherspatially or temporally. The processing unit 114 can be in directelectrical communication through line 112, or alternatively, may beconnected via a wireless communication. Alternatively, the processingunit 114 can be preprogrammed to provide a spatially distributed coolingprofile and/or a time-varying cooling profile. The processing unit 114can include any processor, Programmable Logic Controller, DistributedControl System, and the like.

In another aspect, the processing unit 114 can be in electricalcommunication with an input device 118, an output device 120, and/or acontrol panel 122. The input device 118 can include a keyboard, a mouse,a touch screen, a push button, a switch, a potentiometer, and any otherdevice suitable for accepting user input. The output device 120 caninclude a display screen, a printer, a medium reader, an audio device,and any other device suitable for providing user feedback. The controlpanel 122 can include indicator lights, numerical displays, and audiodevices. In alternative embodiments, the control panel 122 can becontained on the cooling device 104. In the embodiment shown in FIG. 4 ,the processing unit 114, power supply 110, control panel 122, coolingunit 106, input device 118, and output device 120 are carried by a rack124 with wheels 126 for portability. In alternative embodiments, theprocessing unit 114 can be contained on the cooling device 104. Inanother embodiment, the various components can be fixedly installed at atreatment site.

FIGS. 5-8 are isometric views of one preferred cooling device 104. Inthis embodiment, the cooling device 104 includes a control systemhousing 202 and cooling element housings 204 a-g. The control systemhousing 202 includes a sleeve 308 (FIG. 9 ) that may slide into collar310 and/or may mechanically attach to the cooling element housings. Thecooling element housings 204 a-g are connected to heat exchangingelements (not shown) by attachment means 206. The attachment means canbe any mechanical attachment device such as a screw or pin as is knownin the art. The plurality of cooling element housings 204 a-g can havemany similar features. As such, the features of the first coolingelement housing 204 a are described below with reference symbolsfollowed by an “a,” corresponding features of the second cooling elementhousing 204 b are shown and noted by the same reference symbol followedby a “b,” and so forth. The cooling element housing 204 a can beconstructed from polymeric materials, metals, ceramics, woods, and/orother suitable materials. The example of the cooling element housing 204a shown in FIGS. 5-8 is generally rectangular, but it can have any otherdesired shape.

The cooling device 104 is shown in a first relatively flat configurationin FIG. 5 ; in a second slightly curved configuration in FIG. 6 ; and ina third curved configuration in FIG. 7 . As shown in FIGS. 6 and 7 ,each segment of the cooling element housings 204 a-g are rotatablyconnected to adjacent segments and moveable about connection 207 a-f toallow the cooling device 104 to curve. The connection 207 a-f, forexample, can be a pin, a ball joint, a bearing, or other type ofrotatable joints. The connection 207 can accordingly be configured torotatably couple the first cooling element housing 204 a to the secondcooling element housing 204 b. According to aspects of the invention,the first cooling element housing 204 a can rotate relative to thesecond cooling element housing 204 b (indicated by arrow A), eachadjacent moveable pair of cooling elements being such that, for example,the angle between the first and second cooling element housings 204 aand 204 b can be adjusted up to a particular angle, for example 45°. Inthis way, the cooling device is articulated such that it can assume acurved configuration conformable to the skin of a subject.

One advantage of the plurality of rotatable heat exchanging surfaces isthat the arcuate shape of the cooling device may concentrate the heattransfer in the subcutaneous region. For example, when heat exchangingsurfaces are rotated about a body contour of a subject, the arcuateshape can concentrate heat removal from the skin.

The control system housing 202 can house a processing unit forcontrolling the cooling device 104 and/or fluid lines 108 a-b and/orelectrical power and communication lines. The control system housing 202includes a harness port 210 for electrical and supply fluid lines (notshown for purposes of clarity). The control system housing 202 canfurther be configured to serve as a handle for a user of the coolingdevice 104. Alternatively, the processing unit may be contained at alocation other than on the cooling device.

As shown in FIGS. 5-7 , the cooling device 104 can further include ateach end of the cooling device 104 retention devices 208 a and 208 bcoupled to a frame 304. The retention devices 208 a and 208 b arerotatably connected to the frame by retention device coupling elements212 a-b. The retention device coupling elements 212 a-b, for example,can be a pin, a ball joint, a bearing, or other type of rotatablejoints. Alternatively, the retention devices 208 a and 208 b can berigidly affixed to the end portions of the cooling element housings 204a and 204 g. Alternately, the retention device can attach to controlsystem housing 202.

The retention devices 208 a and 208 b are each shown as tabs 214, eachhaving a slot 216 therein for receiving a band or elastomeric strap (notshown for purposes of clarity) to retain the cooling device 104 in placeon a subject 101 during treatment. Alternatively, the cooling device maynot contain any attached retention device and may be held in place byhand, may be held in place by gravity, or may be held in place with aband, elastomeric strap, or non-elastic fabric (e.g., nylon webbing)wrapped around the cooling device 104 and the subject 101.

In an alternate embodiment, the device may be a device for applyingpressure, or otherwise inducing vasoconstriction, rather than a coolingdevice.

As shown in FIGS. 5-7 , the cooling element housings 204 a-g have afirst edge 218 and an adjacent second edge 220 of a reciprocal shape toallow the cooling device 104 to mate and, thus, configure in a flatconfiguration. The first edge 218 and the second edge 220 are generallyangular in the Figures; however, the shape could be curved, straight, ora combination of angles, curves, and straight edges that provide areciprocal shape between adjacent segments of the cooling elementhousings 204 a-g.

FIG. 8 shows an isometric view of an alternative cooling device 104 inaccordance with embodiments of the invention suitable for use in thesystem 100. In this embodiment, the cooling device 104 includes aplurality of heat exchanging elements 300 a-g contained within aflexible substrate 350. As described with respect to FIGS. 5-7 ,adjacent heat exchanging elements 300 a-g are fluidly coupled in seriesby fluid lines 328.

The cooling elements 302 a-g can be affixed to the flexible substrate350, or may be embedded in the flexible substrate 350. The flexiblesubstrate 350 can be constructed from polymeric materials, elastomericmaterials, and/or other suitable materials. The flexible substrate 350can further be an elastomer such as silicone or urethane or can be afabric, such as nylon. The flexible substrate 350 can also be a thinpolymer such as polypropylene or ABS. The example of the flexiblesubstrate 350 shown in FIG. 8 is generally rectangular, but can have anyother desired shape, including a matrix configuration or an anatomyspecific shape.

As designed, the interface members and cooling elements protect thethermoelectric coolers while maintaining good heat transfer between thethermoelectric coolers and the skin. The interface members are sizedsuch that they do not present a significant thermal mass. In one design,each thermoelectric cooler could be 1″×1.5″. The interface member oraluminum plate could also be 1″×1.5″ with a thickness of 0.04″. If thethermoelectric coolers' cooling power is approximately 10 W, which isappropriate based on the heat flux expected to conduct from the skin,then the aluminum plate would cool from an ambient temperature of 20° C.to a treatment temperature of −10° C. in about 7 seconds. The change ininternal energy of the plate is described by the following equation:

ΔE=ρ·V·C·ΔT

where ΔE is the change in internal energy, ρ is the material density, Vis the material volume, C is the heat capacity of the material, and ΔTis the temperature change. In the problem described above, the volume ofthe aluminum plate is V=1 in×1.5 in×0.04 in or 0.06 in³ (9.8×10-7 m3).For a typical grade of aluminum, C°=875 J/kg*° C. and ρ=2770 kg/m3.Solving the equation using these constants:

ΔE=2770 kg/m3*9.8×10-7 m3*875 J/kg*° C.*30° C.=71.3 J

If the thermoelectric coolers have a cooling power of 10 W, then 71.3 Jcould be removed from the aluminum plate in 7.1 seconds, as is shown inthe calculation below:

71.3 J/(10 J/second)=7.13 seconds

A small gap or recess in the frame at the skin surface may be includedin one embodiment. Prior to applying the cooling device to the skin, athermally conducting fluid or coupling agent can be applied to thedevice and to the skin to minimize contact resistance and increase heattransfer between the cooling device and the skin. This coupling agentwill fill the gap in the cooling device and allow for limited lateralconduction between the thermoelectric coolers' plates. This will createa more uniform temperature gradient across the surface area of the skinwhen the cooling is applied to the skin.

The lipid-rich cells can be affected by disrupting, shrinking,disabling, destroying, removing, killing, or otherwise being altered.Without being bound by theory, selectively affecting lipid-rich cells isbelieved to result from localized crystallization of lipids attemperatures that do not induce crystallization in non-lipid-rich cells.The crystals can disrupt or alter the bi-layer membrane of lipid-richcells to selectively damage these cells. Thus, damage of non-lipid-richcells, such as dermal cells, can be avoided at temperatures that inducecrystal formation in lipid-rich cells. Cooling is also believed toinduce lipolysis (e.g., fat metabolism) of lipid-rich cells to furtherenhance the reduction in subcutaneous lipid-rich cells. Vasoconstrictionby means other than cooling are contemplated by the present invention.For example, pressure or administration of certain drugs may be employedto cause ischemia.

The coupling agent may be applied to the skin or to the interface memberto provide improved thermal conductivity. The coupling agent may includepolypropylene glycol, polyethylene glycol, propylene glycol, and/orglycol. Glycols, glycerols, and other deicing chemicals are efficientfreezing-point depressants and act as a solute to lower the freezingpoint of the coupling agent. Propylene glycol is one exemplary componentof deicer or non-freezing coupling agents. Other components includepolypropylene glycol (PPG), polyethylene glycol (PEG), polyglycols,glycols, ethylene glycol, dimethyl sulfoxide, polyvinyl pyridine,calcium magnesium acetate, sodium acetate, ethanol and/or sodiumformate. The coupling agent preferably has a freezing point in the rangeof −40° C. to 0° C., more preferably below −10° C. as further describedin U.S. Provisional Application 60/795,799, entitled Coupling Agent ForUse With a Cooling Device For Improved Removal of Heat From SubcutaneousLipid-Rich Cells, filed on Apr. 28, 2006, herein incorporated in itsentirety by reference.

FIG. 10 is a functional diagram showing exemplary software modules 940suitable for use in the processing unit 114. Each component can be acomputer program, procedure, or process written as source code in aconventional programming language, such as the C programming language,and can be presented for execution by the CPU of processor 942. Thevarious implementations of the source code and object code can be storedon a computer-readable storage medium or embodied on a transmissionmedium in a carrier wave. The modules of processor 942 can include aninput module 944, a database module 946, a process module 948, an outputmodule 950, and, optionally, a display module 951. In anotherembodiment, the software modules 940 can be presented for execution bythe CPU of a network server in a distributed computing scheme.

In operation, the input module 944 accepts an operator input, such asprocess setpoint and control selections, and communicates the acceptedinformation or selections to other components for further processing.The database module 946 organizes records, including operatingparameters 954, operator activities 956, and alarms 958, and facilitatesstoring and retrieving of these records to and from a database 952. Anytype of database organization can be utilized, including a flat filesystem, hierarchical database, relational database, or distributeddatabase, such as provided by a database vendor such as OracleCorporation, Redwood Shores, Calif.

The process module 948 generates control variables based on sensorreadings 960, and the output module 950 generates output signals 962based on the control variables. For example, the output module 950 canconvert the generated control variables from the process module 948 into4-20 mA output signals 962 suitable for a direct current voltagemodulator. The processor 942 optionally can include the display module951 for displaying, printing, or downloading the sensor readings 960 andoutput signals 962 via devices such as the output device 120. A suitabledisplay module 951 can be a video driver that enables the processor 942to display the sensor readings 960 on the output device 120.

One interesting feature of a thermoelectric cooler is that if thepolarity of the applied voltage is reversed, the cold side becomes warmand the warm side becomes cold. In this way, the thermoelectric coolermay be employed to increase the blood flow rate and stimulatereperfusion in the cooled tissue. This would cause ischemia-reperfusioninjury and improve the results achieved by the methods described in U.S.Patent Publication No. 2003/0220674 and in U.S. Patent Publication No.2005/0251120.

Regardless of the cooling element type, the cooling element can bemaintained at an average temperature between about −30° C. and about 35°C., preferably from about −20° C. 1 o about 20° C., more preferably fromabout −20° C. to about 10° C., more preferably from about −15° C. toabout 5° C., more preferably from about −10° C. to about 0° C. In oneembodiment, the region is exposed to the cooling element from about 2min to about 60 min, or preferably from about 5 min to about 30 min.

After cooling has been effected or vasoconstriction otherwise induced,the tissue of interest is exposed to an energy source to increase bloodflow. The term “energy source” refers to any known form of energy thatwould increase blood flow in a subject, either by inflammation or othermechanisms. As will be recognized, the energy source can be the samedevice used to effect cooling (as, for example, by changing thetemperature profile of a fluid bath or by reversing polarity on theapplied voltage of a thermoelectric cooler) or a different device.Energy sources according to the invention can supply electromagneticenergy (e.g., light, radiofrequency), thermal energy (e.g., heat) and/ormechanical energy (e.g., physical contact, friction, vibration, soundwaves). In preferred embodiments, the energy source causes the bloodflow rate to increase more rapidly than would occur without the energysource.

The energy source can, for example, be a capacitively coupled RF devicesuch as those in which a power source provides energy to an RF generatorand then to at least one RF electrode. An electronic measuring systemmeasures current, voltage, and temperature via thermal sensors. Thepresent invention utilizes an electronic measuring system driven by acontroller, such as a computer with appropriate software. Variousfeedback or monitoring systems attached to the controller includeultrasonic, thermal, or impedance monitors. Current and voltage are usedto calculate impedance. The output for these monitors is used by thecontroller to control the delivery of RF power. The amount of RF energydelivered controls the amount of RF power.

In one embodiment, the RF energy is provided by an RF electrode coatedwith dielectric material. The use of dielectric coating produces a moreuniform impedance throughout the electrode and causes a more uniformcurrent to flow through the electrode. The resulting effect minimizesedge effects around the edges of the electrode. It is desirable to havethe electrical impedance of the dielectric layer to be higher than thatof the subject tissue. In various embodiments, the impedance of layer32′ at the operating frequency, can be in the range of 200 Ω/cm² orgreater. Suitable materials for a dielectric coating include, but arenot limited to, TEFLON, silicon nitride, polysilanes, polysilazanes,polyimides, KAPTON, antenna dielectrics and other dielectric materialswell known in the art.

In one embodiment, one or more RF electrodes are connected to an RFgenerator. The temperature of the tissue or of RF electrode ismonitored, and the output power of energy source adjusted accordingly.The system can be a closed- or open-loop system to switch power on andoff, as well as modulate the power. A closed-loop system utilizes amicroprocessor to serve as a controller to monitor the temperature,adjust the RF power, analyze the result, feed back the result, and thenmodulate the power. More specifically, a controller governs the powerlevels, cycles, and duration that the radiofrequency energy isdistributed to the individual electrodes to achieve and maintain powerlevels appropriate to achieve the desired treatment. In one embodiment,the controller is an INTEL PENTIUM microprocessor; however it will beappreciated that any suitable microprocessor or general purpose digitalor analog computer can be used to perform one or more of the functionsof controller.

With the use of sensor and feedback control system skin or other tissueadjacent to the RF electrode can be maintained at a desired temperaturefor a selected period of time without causing a shut-down of the powercircuit to electrode due to the development of excessive electricalimpedance at electrode or adjacent tissue. Current and voltage can bemeasured by sensors, and used to calculate impedance and power. Acontrol signal is generated by controller that is proportional to thedifference between an actual measured value, and a desired value. Thecontrol signal is used by power circuits to adjust the power output inan appropriate amount in order to maintain the desired power deliveredat respective RF electrodes.

In a similar manner, temperatures detected at a sensor provide feedbackfor maintaining a selected power. A control signal is generated by acontroller that is proportional to the difference between an actualmeasured temperature and a desired temperature. The control signal isused by power circuits to adjust the power output in an appropriateamount in order to maintain the desired temperature delivered at thesensor.

Examples of methods utilizing RF on a subject are disclosed in U.S. Pat.Nos. 6,413,255 and 5,948,011, the entire disclosures of which areincorporated herein.

Alternatively, the energy source can be vibrational, and delivered by aconventional vibrating device. Such vibratory massagers are known toincrease blood circulation and perfusion. Representative devices includethe Endermologie ES1 device (LPG Systems, Valence, France), VelaSmoothsystem (Syneron Inc, Richmond Hill, Ontario, Canada), and TriActiveLaserdermology system (Cynosure Inc, Chelmsford, Mass., USA).

Alternatively, the energy source can be acoustic, and delivered byultrasound, transducers. Ultrasound energy is well known to thoseskilled in the art to be capable of heating tissue. Treatment devicescan include a high intensity focused ultrasound (HIFU) system—inparticular, a system with a plurality of independently controlledmultiple beam transducer elements that are capable of being focused atthe treatment depths below the skin surface. A HIFU transducer comprisesan army of transducer elements. Each transducer element comprises apiezoelectric element, solid coupling element, and focusing lens. Thetransducer elements may span treatment depths including 0.35 to 3.5 cm.For example, five transducer elements may have focal points of 0.5, 0.8,1.2, 1.9, and 3.0 cm, with correspondingly operate frequencies of 12, 9,7, 5.5, and 4 MHz, respectively. It should be noted that the transducermay comprise different numbers of transducer elements.

The HIFU transducer supplies a predetermined amount of ultrasonic energyper unit distance traveled (not per unit time) for each treatment regionand sensors that detect cavitation and boiling of the fat tissue. TheHIFU transducer can be controlled to determine the desired temperaturethrough feedback mechanisms. For example, a monitored Doppler dynamicsound caused by cavitation or boiling may be used as an indicator to seta power level outputted by the transducer in the HIFU system. Examplesof methods utilizing HIFU on a subject are disclosed in U.S. PatentPublication No. 2006/0122509, U.S. Patent Publication No. 2005/0154431,and U.S. Patent Publication No. 2004/0039312, the entire disclosures ofwhich are incorporated herein.

In one embodiment, the energy source is applied such that the region iswarmed to about normal body temperature. Alternatively, the energysource is applied such that the region is warmed to above normal bodytemperature. Alternatively, the energy source is applied such that theregion is warmed to a temperature warmer than the temperature of thepreviously cooled lipid-rich cells, at least enough to stimulatereperfusion.

The amount of time that the energy source is applied typically dependson the energy source itself. For example, depending on the source, theenergy is applied for from about 1 sec to about 30 min. Preferably, theenergy is applied for from about 1 sec to about 15 min. Skilled artisansare aware of the variables to consider when applying energy to asubject.

In certain embodiments, energy, such as capacitively coupledradiofrequency energy, is applied to the tissue with energy of about 10J/cm² to about 1000 J/cm² is applied to the tissue. Preferably, about 50J/cm² to about 300 J/cm² is applied to the tissue.

Free radical-mediated mechanisms of cellular damage are believed to beinvolved after periods of ischemia and reperfusion. Nishikawa,Ultrastructural Changes and Lipid Peroxidation in RatAdipomusculocutaneous Flap Isotransplants after Normothermic Storage andReperfusion, Transplantation, Vol. 54, 795-801, 1992. More particularly,it is known that fat has a greater predisposition to free radical damagethan skin. Id, Coban, Ischemia-Reperfusion Injury of AdipofascialTissue: An Experimental Study Evaluating Early Histologic andBiochemical Alterations in Rats, Mediators of Inflammation, Vol. 5,304-308, 2005 (fat tissue is more susceptible to ischemic events). Thesestudies look to minimize injury to fat tissue during transplants. Bycontrast, while not intending to be bound by theory, it is believed thatit is beneficial to augment ischemia-reperfusion injury in the adiposetissue, thus enhancing adipose tissue necrosis.

The damage of reperfusion injury is due in part to the inflammatoryresponse of damaged tissues. White blood cells carried to the area bythe newly returning blood release a host of inflammatory factors such asinterleukins as well as free radicals in response to tissue damage. Therestored blood flow reintroduces oxygen within cells that damagescellular proteins, DNA, and the plasma membrane. Damage to the cell'smembrane may in turn cause the release of more free radicals. Suchreactive species may also act indirectly in redox signaling to turn onapoptosis. Redox signaling is the concept that free radicals, reactiveoxygen species (ROS), and other electronically-activated species act asmessengers in biological systems. Leukocytes may also build up in smallcapillaries, obstructing them and leading to more ischemia.

In certain embodiments, the methods of the invention further comprisetreating the region to encourage formation of oxygen radicals. Oxygenradicals are damaging to tissues, and their concentration may beincreased in a number of ways, including locally administering oxygenradical forming compounds (such as bleomycin) and compounds (such as theinterleukins and other immune adjuvants) that stimulate inflammation by,for example, stimulating release of inflammatory mediators and/orleukocyte activity. In yet another embodiment, the method furthercomprises treating the region to encourage formation of intracellularand/or extracellular ion concentrations at other than normal levels.

The present invention provides methods of treating subcutaneous adiposetissue in a region of a subject's body, comprising exposing said regionto a cooling element under conditions effective to cool said tissue; andstimulating reperfusion in the cooled tissue by exposing the tissue toan energy source to increase the blood flow rate to the cooled tissue.In one embodiment, stimulating reperfusion in the tissue causesischemia-reperfusion injury to the tissue. Ischemia-reperfusion injuryin the tissue permanently damages adipocytes present in the tissue.

In some embodiments, the methods further comprise determining the amountof adipocytes present in the tissue. The determination may be madebefore the exposing step, after the exposing step, or both before andafter the exposing step.

In another embodiment, the present invention provides methods oftreating subcutaneous adipose tissue in a region of a subject's body,comprising exposing said region to a cooling element under conditionseffective to cool said tissue; and causing an ischemia-reperfusioninjury to the cooled tissue by exposing the tissue to an energy sourceto increase the blood flow rate to the cooled tissue.

In the foregoing specification, the concepts have been described withreference to specific embodiments. Many aspects and embodiments havebeen described above and are merely exemplary and not limiting. Afterreading this specification, skilled artisans appreciate that otheraspects and embodiments are possible without departing from the scope ofthe invention. Moreover, one of ordinary skill in the art appreciatesthat various modifications and changes can be made without departingfrom the scope of the invention as set forth in the claims below.Accordingly, the specification and figures are to be regarded in anillustrative rather than a restrictive sense, and all such modificationsare intended to be included within the scope of invention.

Benefits, other advantages, and solutions to problems have beendescribed above with regard to specific embodiments. However, thebenefits, advantages, solutions to problems, and any feature(s) that maycause the same to occur or become more pronounced are not to beconstrued as a critical, required, or essential feature of any or allthe claims.

It is to be appreciated that certain features are, for clarity,described herein in the context of separate embodiments, but may also beprovided in combination in a single embodiment. Conversely, variousfeatures that are, for brevity, described in the context of a singleembodiment, may also be provided separately or in any subcombination.Further, reference to values stated in ranges include each and everyvalue within that range.

What is claimed:
 1. A method for selective reduction of lipid-rich cellsin a region of a human subject's body, comprising: exposing an epidermallayer in said region to a cooling element under conditions effective tocool subcutaneous adipose tissue in said region; and increasing a rateof blood flow to the cooled tissue by exposing the tissue to an energysource.
 2. The method of claim 1, further comprising cycling at leastone of the steps of exposing said region to a cooling element andincreasing blood flow.
 3. The method of claim 1, further comprising thestep of increasing vasoconstriction.
 4. The method of claim 1, ‘hereinthe energy source causes the blood flow rate to increase more rapidly’than would occur without the energy source.
 5. The method of claim 1,wherein the cooling element is maintained at an average temperaturebetween about −20° C. and about 5° C.
 6. The method of claim 1, whereinthe region is exposed to the cooling element from about 2 min to about60 min,
 7. The method of claim 1, wherein the cooling element includes athermoelectric cooling element.
 8. The method of claim 1, wherein thecooling element includes a cooling agent circulating through the coolingelement.
 9. The method of claim 1, wherein the energy source provides atleast one of thermal, vibrational, acoustic, and electromagnetic energy.10. The method of claim 1, wherein the energy source provides mechanicalenemy.
 11. The method of claim 1, wherein the energy source is appliedsuch that the region is warmed to at least about normal bodytemperature.
 12. The method of claim 1 wherein the energy source isapplied such that the region is warmed to a temperature warmer than thetemperature of the cooled tissue.
 13. The method of claim 12 wherein theregion is warmed sufficient to stimulate reperfusion.
 14. The method ofclaim 1, wherein the energy is applied for from about 1 sec to about 30min.
 15. The method of claim 1, wherein energy of about 10 J/cm² toabout 1000 J/cm² is applied to the tissue.
 16. The method of claim 1,wherein the steps produce ischemia-reperfusion injury.
 17. The method ofclaim 1, further comprising treating the region to encourage formationof oxygen radicals.
 18. The method of claim 17, wherein the treatingcomprises locally administering oxygen radical forming compounds,stimulating inflammation, stimulating release of inflammatory mediators,or stimulating leukocyte activity.
 19. The method of claim 1, furthercomprising treating the region to encourage formation of intracellularand/or extracellular ion concentrations at other than normal levels. 20.A method of treating subcutaneous adipose tissue in a region of asubject's body, comprising: exposing said region to a cooling elementunder conditions effective to cool said tissue; and stimulatingreperfusion in the cooled tissue by exposing the tissue to an energysource to increase the blood flow rate to the cooled tissue. 21.-29.(canceled)